Brain Structure and Clinical Endpoints in Myotonic Dystrophy Type 2

Project Summary The overall goals of this K23 application are to evaluate the relationship between brain structure and function on cognition and motor performance in myotonic dystrophy type 2 (DM2), and thereby contribute to the Candidate’s preparation to independently lead future research elucidating the neurobiology of DM2. Although

muscle weakness is the key symptom in DM2, almost 70% of patients report that impaired cognition is among the most disabling symptoms, and deeply affects their quality of life. DM2, a multifaceted genetic disorder, results from a CCTG repeat expansion in the cellular nucleic acid binding protein (CNBP) gene, where the

RNA gain-of-function is the main disease mechanism. Although DM2 has several distinctions from myotonic dystrophy type 1 (DM1), they share some genetic and clinical similarities, e.g. substantial cognitive symptoms and muscle weakness. While studies of brain imaging in DM1 have increased over the past decade, relatively

little is known about how DM2 affects brain structure and function as brain imaging studies in DM2 are extremely limited. Results of these studies have had conflicting results because of small sample sizes, lack of quantitative analyses, and discrepancy between cognitive measures. However, most findings suggest that,

compared to controls, cerebral white matter (WM) is primarily affected in DM2, with reduced in WM volume and abnormal WM integrity derived from diffusion tensor imaging (DTI). Emerging evidence has identified tau mis- splicing and tangle pathology in DM2, which has prompted interest in elucidating the role of tau in DM2-related

cognitive impairment. This possibility is underscored by recent studies of relationships between WM integrity and cortical tau deposition and cerebrospinal fluid (CSF) tau in Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD). Nevertheless, no study to date has evaluated the role of tau in DM2. In

sum, despite clear cognitive symptoms that suggest CNS involvement, no studies have meticulously evaluated brain structure and fluid biomarkers of CNS pathology and their relationships to cognitive and motor measures in DM2. In Aim 1, I will evaluate brain morphometry and DTI measures of white matter integrity, including

fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity between 40 adults with DM2 vs. 40 age- and sex-matched control. In Aim 2, I will determine relationships of measures of white matter integrity (cerebral FA and RD) with cognitive and motor endpoints. In Aim 3, I will conduct a pilot proof-of-concept study to

characterize tau profiles in the CSF and plasma of patients with DM2 and associate these findings with measures of brain structure and cognitive endpoints. The proposed integrated research, mentorship, and didactic training, combined with the outstanding research environment at Wake Forest University Health

Sciences, will foster my long-term career goals to become an independent investigator with the knowledge and skills to lead research on the neurobiology of CNS manifestation and ultimately clinical trials that test novel therapies targeting mechanisms to improve outcomes and quality of life in patients with DM2.